Cyclopropane carboxylic acid derivatives

ABSTRACT

Disclosed herein are 2-(p-substituted phenyl)-cyclopropane carboxylic acids, which compounds are useful in alleviating inflammation and pain.

O firmed $46565 Pafiem [151 3,674,832

Sherlock et a1. July 4, 1972 54] CYCLOPROPANE CARBOXYLIC ACID [51]1nt.Cl ..C07c 63/42,C07c 69/76 DERIVATIVES [58] Field of Search..260/515 A, 515 R, 516,470, 2611/46) [72] Inventors: Margaret H.Sherlock, Bloomfield; Nathan Sperber, North Caldwell, both of NJ [SolRclorcnccs Cited [73] Assigncc: Scherlng Corporation, Bloomfield, NJ.UNITED STATES PATENTS 1 1 Filed: g- 2, 1968 3,050,559 8/1962 Burger..2e0/5 15 [2] I App! 754743 Primary Examiner-James A. PattenAtt0rney-Bruce M. Eisen, Stephen B. Coan and Raymond A. I52] U.S. Cl...260/469, 204/158 R, 204/162 R, McDonald 260/448 R, 260/465 E, 260/465F, 260/465 G, 260/465 H, 260/465 R, 260/470, 260/471, 260/473 A, 260/473R, 260/473 S, 260/473 SC, 260/501.11, 260/501.15, 260/515 A, 260/515 P,260/515 R, 260/516, 260/518 R, 260/520, 260/544 M, 260/571, 260/574,260/650 R, 260/651 F, 260/599, 260/651 R, 424/308, 260/600, 424/309,260/609 E, 424/315, 424/316, 260/618 B, 424/317, 424/319,

260/649 D, 260/649 F, 260/649 R. 2601650 F [5 7] ABSTRACT Disclosedherein are 2-(p-substituted phenyl)-cyc1opropa ne carboxylic acids,which compounds are useful in alleviatmg mflammation and pain.

9 Claims, No Drawings CYCLOPROPANE CARBOXYLIC ACID DERIVATIVES Thisinvention relates to compositions of matter which may be consideredchemically as 2-(p-substituted phenyl)- cyclopropane carboxylic acidsand to processes for making and using such compositions.

The invention sought to be patented in one of its composition aspects isdescribed as residing in the concept of a chemical compound having themolecular structure of cyclopropane having a carboxy moiety attached toone of the ring carbon atoms and a phenyl nucleus attached to adifierent carbon atom of the cyclopropane ring; said phenyl nucleusitself being substituted in the para position with either a phenylradical or a saturated lower aliphatic hydrocarbyl radical having atleast one secondary carbon atom. The aforesaid phenyl nucleus canoptionally be further substituted in the ortho or meta positions. Alsoincluded within this concept are the pharmaceutically acceptable saltsand esters of the aforesaid cyclopropane carboxylic acids.

The invention sought to be patented in another of its compositionaspects resides in the concept of a pharmaceutical formulation havinganti-inflammatory and analgesic properties containing a novelcomposition of matter of this invention.

The invention sought to be patented in one of its process aspects isdescribed as residing in those concepts which comprise the reactionsequence of reducing the appropriately para substituted acetophenone toform the corresponding carbinol, followed by dehydrating the latter toform the corresponding p-substituted styrene, and then reacting thelatter with a diazoacetic acid ester (preferably a lower alkyl ester) toform the corresponding ester of the Z-(p-substituted phenyl)-cyclopropane carboxylic acid, followed by hydrolysis of the ester to thedesired acid.

The invention sought to be patented in another of its process aspects isdescribed as residing in the concept of treating and alleviatinginflammation and inflammatory conditions by administering atherapeutically effective quantity of a novel composition of matter ofthis invention. Another process aspect of this invention is the use ofnovel compositions of this invention to cause an analgesic effect.Another process aspect of this invention is the use of the novelcompositions of matter of this invention in combination with otheractive therapeutics to provide desirable complementary effects whenemployed in the treatment of inflammatory conditions and in thetreatment of pain.

A more specific representation of the tangible embodiments of thisinvention are the chemical compositions having the structural formula:

wherein R is a phenyl radical or a saturated lower aliphatic hydrocarbonradical having at least one secondary carbon atom; X is hydrogen,halogen, trifluoromethyl, nitro, lower alkyl, di-lower alkyl amino,lower alkylthio, lower alkoxy or hydroxy, and R is hydrogen, an alkylradical having one to 12 carbon atoms, or a pharmaceutically acceptablecation.

As used herein the term lower aliphatic hydrocarbon radical having atleast one secondary carbon atom means cyclized or branched-chain loweralkyl radicals as illustrated by isopropyl, isobutyl, isoamyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclohexylmethyl and the like.Preferably R is a cycloalkyl radical having five to seven carbon atomsand, most preferably, R is cyclohexyl. X is preferably in the metaposition relative to the cyclopropyl moiety and, most preferably, X ismeta-chloro.

The term pharmaceutically acceptable cation includes any cation whichforms p-substituted cyclopropane carboxylic acid salts which do notcreate any difference in kind of pharmaceutical activity from that shownby the corresponding free acid. Such cations can be used to providegreater solubility or greater ease in formulation than the free acid.Representative of such salts are those wherein the cation is an alkalimetal such as sodium or potassium, ammonium, substituted ammonium suchas diethanolarnmonium or such metal cations as calcium or aluminum.Similarly, the pharmaceutically acceptable esters of the freecyclopropane carboxylic acids are those which are used in pharmaceuticalformulations and which do not create any difference in kind ofpharmaceutical activity from that shown by the free cyclopropanecarboxylic acid. The esters themselves do not change the characteristicapplication of the free acid but merely facilitate application orformulating of the compounds, as for example, by increasing solubility.When hydrolyzed in the body, these esters yield the free cyclopropanecarboxylic acid and a pharmaceutically acceptable alcohol, e.g. ethanol.The R moiety may be further functionally substituted to increasepolarity, solubility, and other such characteristics, such R groupsincluding dialkylaminoalkyl (e.g. dimethylaminoethyl) and glycerolesters. Such esters are considered to be the full equivalent of the freecyclopropane carboxylic acids.

It is to be noted that formula I embraces both cisand transgeometricisomers as well as optical isomers. It is to be understood that thisinvention embraces all such isomers, although it is recognized thatvariations in efficacy are to be expected. The cisisomers, i.e. thosewherein the carboxy moiety and the p-substituted phenyl moiety are onthe same side of the plane of the cyclopropane ring, are preferred.Cisand transisomers of the compounds of this invention can generally beseparated by conventional fractional crystallization techniques or bypreferential hydrolysis of the ester. Generally the trans esterhydrolyzes first and thus it can readily be separated from thecisisomer. A desired dor l-optical isomer can be isolated from theracemate in the conventional manner via salt formation with an opticallyactive resolving base such as d-amphetamine. The techniques of saltformation and separation of the salts as by fractional crystallizationare well known to those skilled in the art.

The compounds of formula I can be prepared by reducing an appropriatelysubstituted acetophenone (ll) with a suitable reducing agent such assodium borohydride and then dehydrating the corresponding carbinol(Ill), as for example, by the use of phosphorous pentoxide or potassiumbisulfate to form the corresponding p-substituted styrene (IV). Areagent such as ethyl diazoacetate can then beadded to product IV toform the corresponding p-substituted cyclopropane carboxylic acid ethylester (V). The latter ester is then hydrolyzed to the free acid (I), asfor example, using potassium hydroxide. This reaction scheme can bedepicted as follows:

wherein R and X have the meanings described above.

The compounds of this invention may also be produced by other processes.For example, the p-substituted styrene (IV) can be oxidized, using forexample potassium permanganate and sodium iodate, to the correspondingp-substituted benzaldehyde. The latter can be condensed with diethylmalonate in the presence of a catalytic amount of piperidine to yieldthe corresponding p-substituted benzal malonate. The latter can be addedalong with an equivalent of sodium hydride to a suspension oftrimethyl-sulfoxonium iodide in dimethylsulfoxide. The product thereof,diethyl-Z-(p-substituted phenyl)- cyclopropane-l,l-dicarboxylate, isthen hydrolyzed with one equivalent of potassium hydroxide in ethanol toyield ethyl 2- (p-substituted phenyl)-l-carboxycyclopropane carboxylate.

The latter is decarboxylated by heating and hydrolyzed with strong baseto give the desired 2-(p-substituted phenyl)- cyclopropanel-carboxylicacid.

The compounds of this invention can also be produced by photolyzing thesolution of the p-substituted styrene (IV) and bromomalononitrile in asuitable solvent such as methylene chloride. Cf. Boldt et al., Ber. 100,p. 1,282 (1967). The product, the corresponding 2-(p-substitutedphenyl)-1,ldicyanopropane, can then be hydrolyzed and thendecarboxylated under the conventional conditions to yield the desiredcyclopropane carboxylic acid.

ln still another manner the compounds of this invention can be preparedby adding bromine to the corresponding p-substituted acetophenone (11)in ether in the presence of a catalytic amount of aluminum chloride. Theresultant p-substituted phenacyl bromide is then condensed with thesodium salt of diethylmalonate to yield the diethyl-p-substitutedphenacyl malonate. The latter is then reduced to the correspondingcarbinol with sodium borohydride in methanol. This carbinol can then bereacted with thionyl chloride in benzene to yield the correspondingchloro malonic ester which can then be reacted with sodium hydride intetrahydrofuran to effect closure of the cyclo-propane ring.

'The resultant p-substituted phenyl cyclopropane dicarboxylate can thenbe hydrolyzed and decarboxylated to the desired free acid in the mannerindicated above.

The following example illustrates a representative method of preparingcompounds ofthis invention:

EXAMPLE 1 Preparation of cisandtrans-2-(3-chloro-4-cyclohexylphenyl)-cyc1opropane carboxylic acid A.l-( 3-Chloro-4-cyclohexylphenyl)-ethan01 17.2 g. of sodium borohydrideare added in portions to a solution of 75.0 g. of3-chloro-4-cyclohexylacetophenone in 675 ml. of methanol. The solutionis refluxed for two and one half hours, concentrated to 175 ml., dilutedwith water and extracted with ether. The ethereal extract is dried oversodium sulfate and concentrated. The desired product is distilledtherefrom at 15 ll52 C and 0.35 mm. Hg.

B. 3-Chloro-4-cyclohexylstyrene 1.8 g. of freshly fused potassiumbisulfate and 0.01 g. of tbutyl catechol are added to a 3-necked flaskwhich is equipped with a dropping funnel and small fractionating column.30 g. of l-(3-chloro-4-cyclohexylphenyl)-ethanol, as above-produced, areadded to this flask at a bath temperature of 230-240 C. and a vacuum of10 mm. The product is collected, dissolved in ether, and dried. Thedesired product is distilled therefrom at l ll 18 C and 0.35 mm. Hg.

( cis +trans) C. Ethyl-2-( 3-chloro-4-cyclohexylphenyl )-cyclopropanecarboxylate 20.5 g. of 3-chloro-4-cyclohexyl styrene are added dropwisewith stirring to 58 ml. of dry xylene heated to 90 C. and containing 16g. of ethyl diazoacetate. After the addition is complete, the solutionis refluxed for 5 hours and concentrated. The desired compounds aredistilled therefrom at l75-187 C and 0.55 mm. Hg.

D. 2-(3-Chloro-4-cyclohexylphenyl)-cyclopropane carboxylic acid 20.8 g.of the crude cis and trans mixture of ethyl-2-(3-chloro-4-cyc1ohexylphenyl)-cyclopropane carboxylate are added to asolution of 140 ml. ethanol containing 4.7 g. of potassium hydroxide and24 ml. of water. The solution is refluxed for 3 hours, concentrated,treated with water and acidified. The crude mixture of cis and transfree acids is purified by fractional crystallization yielding the puretrans, m.p. l7l.5-l73.5 C (upon recrystallization from acetonitrile),and pure cis, m.p. ll7l 19 C (upon recrystallization from hexane).

EXAMPLE 2 Preparation of cisand trans- 2-(p-biphenyl)-cyclopropanecarboxylic acid 15 g. of p-phenylstyrene was reacted with 14.4 g. ofethyl diazoacetate and worked up in the same manner as in steps C and Dof Example 1. The crude hydrolysis reaction product of cis and transfree acids is purified by fractional crystallization yielding the puretrans, m.p. 186-187 C (upon recrystallization from acetonitrile), andpure cis, m.p. l5l-153 C (upon recrystallization from isopropyl ether).

Similarly, by substituting the corresponding p-substituted phenylacetophenone for 3-chloro-4-cyc1ohexylphenyl acetophenone, one cananalogously prepare the corresponding 2-(p-substitutedphenyl)-cyclopropane carboxylic acids, as for example:

cis-2-(p-cyclohexylphenyl)-cyclopropane carboxylic acid,

trans-2-( 3-chloro-4-cyclohexylphenyl )-cyclopropane carboxylic acid,cis-2-(3-chloro-4-cyclopentylphenyl)- cyclopropane carboxylic acid,cis-2-(3-chloro-4- cycloheptylphenyl)-cyclopropane carboxylic acid,cis-2- (3-trifluoromethyl-4-cyclohexylphenyl )-cyclopropane carboxylicacid,

cis-2-(2-iodo-4-cyclohexylphenyl)-cyclopropane carboxylic acid,trans-2-( 3-bromo-4-cyclohexylphenyl cyclopropane carboxylic acid,cis-2-( 3-thiomethyl-4- cyclohexyl)-cyclopropane carboxylic acid,cis-2-(3- chloro-4-isobutylphenyl)-cyclopropane carboxylic acid,trans-2-( 3-nitro-4-isobutylphenyl)-cyclopropane carboxylic acid,trans-2-(3-methoxy-4-biphenyl)-cyclopropane carboxylic acid,cis-2-(3-methyl-4-isopropylphenyl)- cyclopropane carboxylic acid,cis-2-(3-hydroxy-4- isoamylphenyl)-cyclopropane carboxylic acid,trans-2- (3-fluoro-4-cyclohexylmethylphenyl)-cyclopropane carboxylicacid,

cis-2-( 3-chloro-4-cyclopropylmethylphenyl )-cyclopropane carboxylicacid, and cis-2-(p-3-pentylphenyl)- cyclopropane carboxylic acid.

The relief of inflammation by the administration of an antiinflammatoryagent without any untoward side effects being induced by thisanti-inflammatory agent has long been desired. Steroids havingcortisone-like activity have previously been employed to relieveinflammation. The use of steroid therapy, however, suffers from thedrawback of such side effects as electrolyte imbalance, water retentionand the like. The novel compositions of this invention are ratherspecific in their action and are non-steroidal in character, resultingin the relative absence of the side effects attributable to steroidtherapy. The prior art has taught the use of certain non-steroidalcompounds in the treatment of inflammatory conditions, but these havealso been found to exhibit deleterious side effects, typicallyulceration of the gastrointestinal tract. The novel compounds of thisinvention markedly lessen this ulcerative effect and thus they tend toexhibit high functional use indices.

It is known that the potency of a drug in delaying the appearance ofedema in a rats paw is closely correlated with its potency as ananti-inflammatory agent. Based thereon, the Carrageenin InducedInflammation (Carrageenin Paw) Test is recognized as a standardpharmacological test for determining anti-inflammatory activity. TheZ-(p-substituted phenyl)- cyclopropane carboxylic acids described hereinexhibit an activity as evidenced by this test equal to or greater thanthat of the commonly used nonsteroid anti-inflammatory agent,phenylbutazone. Compounds of this invention also tend to exhibit markedand potent analgesic effects. Thus, the p-substituted phenylcyclopropane carboxylic acids described herein are useful in treatinginflammation, especially that associated with rheumatoid andosteoporosis joint diseases, collagen diseases, bursitis, goutyarthritis, spondylitis and the like.

On the basis of standard tests such as the aforesaid Carrageenin PawTest, it is concluded that the effective anti-inflammatory dosage of theactive ingredients of the compositions of this invention is within therange of about 1 to 20 mg. per kg. of mammalian body weight. Similarly,from standard pharmacological observations such as the MouseAntiwrithing Screen, it is concluded that the effective analgesic dosageis also within the range of about 1 to 20 mg. per kg. of mammalian bodyweight. These dosages can be administered once daily or can be dividedand taken at given intervals during the day. In each specific instance,however, the attending diagnostician will determine the dosage, amountand frequency taking into account related health factors of the subject.

The compounds of this invention may be administered alone or combinedwith other medicaments. In any event, a suitable pharmaceuticallyacceptable carrier is generally employed. A carrier is selectedaccording to the route of administration to be used as well as accordingto the physical properties of the compounds and standard pharmaceuticalpractice. In a preferred embodiment the compositions of this inventionare administered orally, although parenteral and topical administrationare also contemplated. The preparations containing the activeingredients of this invention may be in the form of tablets, capsules,syrups, elixirs, suspensions, ointments, creams and the like.

In the formulations of pharmaceutical preparations there can be employedsuch substances which do not react with the compounds, as for example,water, gelatin, lactose, starches, magnesium stearate, talc, vegetableoils, benzyl alcohols, gums, polyalkylene glycols, and petroleum jelly.The following examples show typical tablet, capsule and parenteralformulations incorporating the tangible embodiments of this invention.The formulations are illustrative merely and no limitation is intended.

EXAMPLE 3 Enteric Coated Tablet Formulations Formula MgJcoreCis-2[3-chloro-4-cyclohexylphenylj -cyclopropane carboxylic acid 100.0Citric acid 1.0 Lactose, USP 33.5 Dicalcium phosphate 70.0 Pluronic F-6830.0 Sodium lauryl sulfate 15.0 Polyvinylpyrrolidone 15.0 Carbowax 15004.5 Carbowax 6000 45.0 3A alcohol, 50 ml./1000 cores Corn starch 30.0Dry:

Sodium lauryl sulfate 3.0

Magnesium stearate 3.0

Tablet weight 350.0

Procedure The 2-[ 3-chloro-4-cyclohexylphenyl]- cyclopropane carboxylicacid is mixed with the citric acid, lactose, dicalcium phosphate,pluronic and sodium lauryl sulfate. The above mixture is screenedthrough a No. 60 screen and damp granulated with an alcoholic solutionconsisting of polyvinylpyrrolidone, Carbowax 1,500 and 6,000. Addadditional alcohol, if necessary, to bring powders to a pasty mass. Addcorn starch and continue mixing until uniform granules are formed. Passthrough a No. 10 screen, tray and dry in oven at 100 C. for 12-14 hours.Reduce dried granulation through a No. 16 screen, add sodium laurylsulfate and magnesium sulfate, mix and compress into desired shape on atablet machine.

Coating The above cores are treated with a lacquer and dusted with taleto prevent moisture adsorption. Sub-coat layers are added to round outthe core. A sufficient number of lacquer coats are applied to make thecore enteric. Additional sub-coats and smoothing coats are applied tocompletely round out and smooth the tablet. Color coats are applieduntil desired shade is obtained. After drying the coated tablets arepolished to give the tablets an even gloss.

EXAMPLE 4 Capsule Formulation Formula Mg.capsuleCis-2-[3-chloro-4-cyclohexylphenyl] -cyclopropane carboxylic acid 100.00Citric acid 1.00 Pluronic, F-68 40.00 Sodium lauryl sulfate 20.00Lactose 238.00 Magnesium stearate 1.00 Total: 400.00

Procedure: Mix together 2-[3-chloro-4-cyclohexylphenyl]- cyclo-propanecarboxylic acid, citric acid, pluronic, sodium lauryl sulfate andlactose. Pass through a No. screen. Add magnesium stearate, mix andencapsulate into the proper size 2 piece gelatin capsule.

EXAMPLE 5 Parenteral Suspension Purified water ad q.s. 1 ml.

Sterile micro-precipitate 2-[3-chloro-4-cyclohexylphenyl]- cyclopropanecarboxylic acid (alternatives micronized steam sterilized or micronizedethylene oxide sterilized) is dispersed in a 10X sterile filteredconcentrate of Tween 80 and sodium citrate. When dispersed a 1.33Xsterile filtered vehicle of the remaining components is added. Whenuniformly dispersed sufficient water for injection is added to finalvolume. The product is then stored under aseptic conditions untilpackaged into multiple dose vials.

Numerous variations of the above-described compositions and methods willbe apparent to one skilled in the art within the spirit of the presentinvention.

What is claimed is:

l. A composition of matter of the formula:

wherein R is a cycloalkyl radical having five to seven carbon atoms; Xis hydrogen, halogen, trifluoromethyl, lower alkyl or thiomethyl; and Ris hydrogen, an alkyl radical having one to 12 carbon atoms or apharmaceutically acceptable cation.

2. A composition according to claim 1 wherein R is cyclohexyl.

3. A composition according to claim 1 wherein R is hydrogen.

4. A composition according to claim 1 wherein R is ethyl.

5. A composition according to claim 1 wherein the X substituent is in aposition meta to the cyclopropane carboxylic acid substituent.

6. A composition according to claim 5 wherein R is cyclohexyl.

7. A composition according to claim 1 wherein the carboxy moiety and thep-substituted phenyl moiety are cisto each other.

8. A composition according to claim 1, said composition being cist2-(3-chloro-4-cyclohexylphenyl)-cyclopropane carboxylic acid.

9. A composition according to claim 5 wherein X is chloro.

2. A composition according to claim 1 wherein R is cyclohexyl.
 3. Acomposition according to claim 1 wherein R'' is hydrogen.
 4. Acomposition according to claim 1 wherein R'' is ethyl.
 5. A compositionaccording to claim 1 wherein the X substituent is in a position meta tothe cyclopropane carboxylic acid substituent.
 6. A composition accordingto claim 5 wherein R is cyclohexyl.
 7. A composition according to claim1 wherein the carboxy moiety and the p-substituted phenyl moiety arecis- to each other.
 8. A composition according to claim 1, saidcomposition being cis-2-(3-chloro-4-cyclohexylphenyl)-cyclopropanecarboxylic acid.
 9. A composition according to claim 5 wherein X ischloro.